Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype
- Mickaël Ohanna1,
- Mickaël Cerezo1,5,
- Nicolas Nottet2,
- Karine Bille1,
- Robin Didier1,
- Guillaume Beranger1,
- Baharia Mograbi3,
- Stéphane Rocchi1,
- Laurent Yvan-Charvet4,
- Robert Ballotti1,6 and
- Corine Bertolotto1,6
- 1U1065, Institut National de la Santé et de la Recherche Médicale (INSERM), Biology and Pathologies of Melanocytes, Equipe Labellisée L'Association pour la Recherche sur le Cancer (ARC) 2015, Université Nice Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France;
- 2Université Nice Côte d'Azur, INSERM, C3M, 06204 Nice, France;
- 3U1081, INSERM, Institute of Research on Cancer and Ageing of Nice (IRCAN), Equipe Labellisée ARC, Université Nice Côte d'Azur, UMR7284, Centre National de la Recherche Scientifique (CNRS), 06107 Nice, France;
- 4U1065, INSERM, Team ATIP-Avenir, Université Nice Côte d'Azur, INSERM, C3M, 06204 Nice, France
- Corresponding author: bertolot{at}unice.fr
-
↵6 These authors contributed equally to this work.
Abstract
In BRAFV600E melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD+) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies. Therefore, NAMPT, the key enzyme in the NAD+ salvage pathway, appears as a rational target in targeted therapy-resistant melanoma cells and a key player in phenotypic plasticity of melanoma cells.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.305854.117.
- Received August 8, 2017.
- Accepted March 5, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
